Approaches to the synthesis of modified taxols

Investigation on the synthesis of the C-13 side chain of taxol was carried out in order to prepare modified taxol derivatives by coupling of the side chain acid chloride to a suitably protected baccatin III. The side chain was prepared by the Darzens condensation. Acylation of baccatin III was performed with simple acylating agents and extensive studies of the ¹H NMR and ¹³C NMR spectra of various acylbaccatins III were carried out aided by homonuclear and heteronuclear COSY experiments. This work led to the unambiguous assignment of the ¹H NMR and ¹³C NMR spectra of these compounds. Coupling of more bulky side chains to 7-(2,2,2-trichloroethyloxycarbonyl) baccatin III was difficult and yields were poor. Conventional methods, using triethylamine or pyridine with 4-dimethylaminopyridine in the coupling reaction of 3- phenylpropanoyl chloride and 7-(2,2,2-trichloroethyloxycarbonyl) baccatin III led to the desired coupled product in low yield together with two coupled compounds possessing more than one phenylpropanoyl group on the C-13 side chain. When the coupling reaction was performed in the presence of silver cyanide in refluxing toluene, only 13-(3-phenylpropanoyl) baccatin III was obtained. However, these two methods were not successful in the coupling reaction of 2-acetyl-3- phenyllactyl chlorlde with 7-(2,2,2-trichloroethyloxycarbonyl) baccatin III. Preliminary studies on the cleavage of the N-acyl group at the C-3' position of taxol and cephalomannine were performed. Taxol reacted with zinc bromide in chloroform-methanol solution to produce 10- deacetyl-7-epitaxol and 10-deacetyltaxol. No cleavage of the N-acyl group was detected in this case and in other reactions in which taxol was treated with various selective reagents. Other attempts involved the conversion of cephalomannine to its ozonolysis products with a pyruvyl group at the 3’-NH group. A method of cleavage of the N-pyruvyl group has not yet been found, however.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Polytechnic Institute and State University

Year dc:date.issued

1986

Author dc:creator

• Jitrangsri, Chote

Chair dc:contributor.committeechair

• Kingston, David G. I.

Committee members dc:contributor.committeemember

• Bell, Harold M.
• Harris, Paul J.
• Wolfe, J.F.
• Hanson, Brian E.

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Handle dc:identifier.uri

http://hdl.handle.net/10919/49801

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/49801